Researchers at the University of California, San Francisco (UCSF) have discovered a gene mutation in fruit flies that alters sensitivity to alcohol.

The findings, reported in the October 6 issue of the journal Cell, may have implications for human studies seeking to understand innate differences in people's tolerance for alcohol. The research was supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA) of the National Institutes of Health (NIH), part of the U.S. Department of Health and Human Services.

The study was authored by Adrian Rothenfluh, Ph.D., and colleagues in the laboratory of Ulrike Heberlein, Ph.D., at UCSF, in collaboration with researchers at the Ernest Gallo Clinic & Research Center. The scientists examined the behavior of fruit flies (Drosophila) exposed to alcohol. Ordinarily, at low doses of alcohol fruit flies increase their activity, while high doses have a sedative effect. However, the researchers found some fruit flies were much more resistant to alcohol sedation. These flies continued to move about much longer than typical fruit flies exposed to the same amount of alcohol. The scientists subsequently identified key differences in a particular gene associated with this behavior. The mutation also altered the flies' sensitivity to cocaine and nicotine as well. Because this gene variant affected the behavioral response to substances of abuse, the researchers dubbed it white rabbit--a reference to the title of a 1960s song about drug-induced changes.

"This study describes key molecular pathways and gene interactions that control alcohol sensitivity," said NIAAA Director Ting-Kai Li, M.D. "These significant clues about the fruit fly's behavioral response may translate into useful tools to advance the search for human genes involved in sensitivity to alcohol. Insights about sensitivity, or acute tolerance, are especially important because we know that people who are less sensitive to alcohol's impact are at greater risk for becoming alcohol dependent," he said.

The researchers exposed fruit flies to vaporized alcohol and monitored their behavior and motion patterns with sensitive tracking instruments. They isolated the flies that were less sensitive to alcohol's sedative effects. By breeding subsequent populations of mutant flies, the scientists identified the particular genetic mutation.

The researchers further showed that the white rabbit mutation disrupted the function of the RhoGAP18B gene. They also isolated a number of gene variants of RhoGAP18B, each of which had a distinctly different effect on the response to alcohol. Manipulating these genetic variants, the researchers generated flies with greater and lesser sensitivity to alcohol's sedative and stimulant effects.

The research team also detailed how signaling proteins encoded by the RhoGAP18B gene variants played an important role in reorganizing components of the adult fruit fly's central nervous system, which in turn affected the flies' behavior. Dr. Rothenfluh said the research team concluded that the RhoGAP18B gene is intimately involved in regulating behavioral responses to alcohol exposure.

The findings have implications for researchers seeking corresponding genes and molecular pathways in other animal models and humans. Antonio Noronha, Ph.D., director of NIAAA's Division of Neuroscience and Behavior, said, "If we can characterize similar genetic differences and neurobehavioral responses that underlie acute tolerance in humans, that could potentially provide new targets for the development of drugs to treat alcohol dependence."

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